Development of Innovative Antibody Drugs using Multifunctional Albumin as a Carrier for Low-molecular-weight Antibodies

• Project/Area Number: 18K06810
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Sojo University
• Principal Investigator: Otagiri Masaki 崇城大学, 薬学部, 特任教授 (80120145)
• Co-Investigator(Kenkyū-buntansha): 森岡 弘志 熊本大学, 大学院生命科学研究部(薬), 教授 (20230097) ; 田口 和明 慶應義塾大学, 薬学部(芝共立), 准教授 (90621912)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: アルブミン / 抗体医薬 / 体内動態 / タンパク工学 / がん治療 / 担体 / 送達システム / 抗腫瘍効果 / 融合技術 / 低分子抗体融合体 / 低分子抗体医薬 / 多機能性アルブミン / 低分子抗体

Outline of Final Research Achievements

In this study, we attempted to develop a low-molecular-weight antibody delivery system using functional albumin as a carrier, with the ultimate goal of creating next-generation antibodies with excellent cost-effectiveness and versatility. As a result, it was found that the fusion resulted in a significant improvement in blood retention and enhanced migration into tumour tissues, indicating that the system acquired kinetic properties suitable for anticancer drugs. Furthermore, analysis of the penetration into the tumour tissue showed that the fusion reached deep into the tissue.

Academic Significance and Societal Importance of the Research Achievements

本研究でアルブミン融合技術を低分子抗体医薬の担体開発に活用する革新的な抗体医薬は、既存の抗体製剤よりも、治療効果の向上、投与量や投与回数の低減化を実現するうえ、患者のQOL改善や医療スタッフの負担軽減という観点からも医療科学的に意義深い。また、本抗体作製方法は新たな低分子抗体に対しても容易に応用可能なため、汎用性が非常に高く、開発・製造コストを低減化できる利点があり、医療経済学上は勿論、社会的な貢献も高いと考えられる。

Research Products

• [Journal Article] Nitric oxide facilitates the targeting Kupffer cells of a nano-antioxidant for the treatment of NASH. (2022)
  • Author(s): Sonoda K, Wakayama T, Kinoshita M, Shuto T, Kai H, Tanaka M, Sasaki Y, Iwakiri Y, Otagiri M
  • Journal Title: J Control Release Volume: 341 Pages: 457-474
  • DOI: 10.1016/j.jconrel.2021.11.039
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] When Albumin Meets Liposomes: A Feasible Drug Carrier for Biomedical Applications. (2021)
  • Author(s): Taguchi K, Okamoto Y, Matsumoto K, Otagiri M, Chuang VTG.
  • Journal Title: Pharmaceuticals (Basel) Volume: 14 Issue: 4 Pages: 296-296
  • DOI: 10.3390/ph14040296
  • Peer Reviewed
• [Journal Article] A mannosylated ,PEGylated albumin as a drug delivery system for the treatment of cancer stroma cells. (2021)
  • Author(s): Mizuta Y, Maeda H, Ishima T, Minayoshi Y, Ichimizu S, Kinoshita R, Fujita I, Kai T, Hirata H, Nakamura T, Saruwari J, Arima H, Watanabe H, Otagiri M, Maruyama T
  • Journal Title: Adv Funct Mater Volume: 31 Issue: 43 Pages: 2104136-2104136
  • DOI: 10.1002/adfm.202104136
  • Peer Reviewed
• [Journal Article] Reduction-responsive and multi-drug deliverable albumin nanoparticles: an antitumor drug to Abraxane_ against human pancreatic tumor-bearing mice (2021)
  • Author(s): Naoki Hirakawa, Yu Ishima, Ryo Kinoshita, Ryuto Nakano, Victor Tuan Giam Chuang, Hidenori Ando, Taro Shimizu, Keiichiro Okuhira, Toru Maruyama, Masaki Otagiri, Tatsuhiro Ishida
  • Journal Title: ACS Applied Bio Materials Volume: 268 Issue: 5 Pages: 4302-4309
  • DOI: 10.1021/acsabm.1c00110
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Therapeutic Effect of Human Serum Albumin Dimer-Doxorubicin Complex against Human Pancreatic Tumors. (2021)
  • Author(s): Kinoshita R, Ishima Y, Chuang VTG, Watanabe H, Shimizu T, Ando H, Okuhira K, Otagiri M, Ishida T, Maruyama T
  • Journal Title: Pharmaceutics. Volume: 13 Issue: 8 Pages: 1209-1209
  • DOI: 10.3390/pharmaceutics13081209
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Molecular recognition of a single-chain Fv antibody specific for GA-pyridine, an advanced glycation end-product (AGE), elucidated using biophysical techniques and synthetic antigen analogues. (2021)
  • Author(s): Kobashigawa, Y., Ohara, T., Morita, K., Toyota, Y., Nakamura, T., Kotani. S., Arimori, T., Yamauchi, S., Liu, C., Kitazaki, M., Wakeyama-Miyazaki, Y., Suwa, Y., Uchida-Kamekura, M., Fukuda, N., Sato, T., Nakajima, M., Takagi, J., Yamagata, Y., and Morioka, H
  • Journal Title: J. Biochem Volume: 170 Issue: 3 Pages: 379-387
  • DOI: 10.1093/jb/mvab056
  • NAID: 40022721879
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pharmacokinetics of 4′-cyano-2′-deoxyguanosine, a novel nucleoside analog inhibitor of the resistant hepatitis B virus, in a rat model of chronic kidney disease (2021)
  • Author(s): Hashimoto Mai、Taguchi Kazuaki、Imoto Shuhei、Yamasaki Keishi、Mitsuya Hiroaki、Otagiri Masaki
  • Journal Title: Journal of Infection and Chemotherapy Volume: 27 Issue: 5 Pages: 702-706
  • DOI: 10.1016/j.jiac.2020.12.014
  • Peer Reviewed / Open Access
• [Journal Article] Interaction of Benzbromarone with Subdomains IIIA and IB/IIA on Human Serum Albumin as the Primary and Secondary Binding Regions (2021)
  • Author(s): Yamasaki Keishi、Kawai Akito、Sakurama Keiki、Udo Nagiko、Yoshino Yuta、Saito Yuki、Tsukigawa Kenji、Nishi Koji、Otagiri Masaki
  • Journal Title: Molecular Pharmaceutics Volume: 18 Issue: 3 Pages: 1061-1070
  • DOI: 10.1021/acs.molpharmaceut.0c01004
  • Peer Reviewed / Open Access
• [Journal Article] Effect of Cinacalcet on the Redox Status of Albumin in Secondary Hyperparathyroidism Patients Receiving Hemodialysis (2020)
  • Author(s): Imafuku Tadashi、Tanaka Motoko、Tokunaga Koki、Miyamura Shigeyuki、Kato Hiromasa、Tanaka Shoma、Nakano Takehiro、Hirata Kenshiro、Kadowaki Daisuke、Maeda Hitoshi、Matsushita Kazutaka、Otagiri Masaki、Komaba Hirotaka、Fukagawa Masafumi、Watanabe Hiroshi、Maruyama Toru
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 43 Issue: 10 Pages: 1583-1590
  • DOI: 10.1248/bpb.b20-00472
  • NAID: 130007920876
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2020-10-01
  • Peer Reviewed / Open Access
• [Journal Article] Drug Delivery System for Refractory Cancer Therapy <i>via</i> an Endogenous Albumin Transport System (2020)
  • Author(s): Ishima Yu、Maruyama Toru、Otagiri Masaki、Ishida Tatsuhiro
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 68 Issue: 7 Pages: 583-588
  • DOI: 10.1248/cpb.c20-00026
  • NAID: 130007867325
  • ISSN: 0009-2363, 1347-5223
  • Year and Date: 2020-07-01
  • Peer Reviewed / Open Access
• [Journal Article] Effects of Oxidation of Human Serum Albumin on the Binding of Aripiprazole (2020)
  • Author(s): Sakurama Keiki、Nishi Koji、Chuang Victor Tuan Giam、Hashimoto Mai、Yamasaki Keishi、Otagiri Masaki
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 43 Issue: 6 Pages: 1023-1026
  • DOI: 10.1248/bpb.b20-00205
  • NAID: 130007850247
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2020-06-01
  • Peer Reviewed / Open Access
• [Journal Article] Serum Albumin, Lipid and Drug Binding (2020)
  • Author(s): Nishi Koji、Yamasaki Keishi、Otagiri Masaki
  • Journal Title: Subcell Biochem Volume: 94 Pages: 383-397
  • DOI: 10.1007/978-3-030-41769-7_15
  • ISBN: 9783030417680, 9783030417697
  • Peer Reviewed
• [Journal Article] Characterization of the Interaction of Daptomycin With Site II on Human Serum Albumin (2020)
  • Author(s): Yamasaki Keishi、Sakurama Keiki、Nishi Koji、Watanabe Hiroshi、Maruyama Toru、Seo Hakaru、Otagiri Masaki、Taguchi Kazuaki
  • Journal Title: Journal of Pharmaceutical Sciences Volume: 109 Issue: 9 Pages: 2919-2924
  • DOI: 10.1016/j.xphs.2020.06.011
  • Peer Reviewed / Open Access
• [Journal Article] Assessing cytochrome P450-based drug-drug interactions with hemoglobin-vesicles, an artificial red blood cell preparation, in healthy rats (2020)
  • Author(s): Tokuno Masahiro、Taguchi Kazuaki、Sakai Hiromi、Ohtsuki Sumio、Yamasaki Keishi、Otagiri Masaki
  • Journal Title: Drug Metabolism and Pharmacokinetics Volume: 35 Issue: 5 Pages: 425-431
  • DOI: 10.1016/j.dmpk.2020.06.005
  • NAID: 50014592884
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of cytochrome P450-based drug metabolism in hemorrhagic shock rats that were transfused with native and an artificial red blood cell preparation, Hemoglobin-vesicles (2020)
  • Author(s): Tokuno Masahiro、Taguchi Kazuaki、Sakai Hiromi、Ohtsuki Sumio、Yamasaki Keishi、Otagiri Masaki
  • Journal Title: Drug Metabolism and Pharmacokinetics Volume: 35 Issue: 5 Pages: 417-424
  • DOI: 10.1016/j.dmpk.2020.06.004
  • NAID: 50014592883
  • Peer Reviewed / Open Access
• [Journal Article] Hepatic Cytochrome P450 Profiles in Hemorrhagic Shock Model Rats After Transfusion With Stored Red Blood Cells (2020)
  • Author(s): Tokuno Masahiro、Taguchi Kazuaki、Yamasaki Keishi、Otagiri Masaki
  • Journal Title: Journal of Pharmaceutical Sciences Volume: 109 Issue: 11 Pages: 3490-3495
  • DOI: 10.1016/j.xphs.2020.08.015
  • Peer Reviewed / Open Access
• [Journal Article] Synthesis and In Vitro Assessment of pH-Sensitive Human Serum Albumin Conjugates of Pirarubicin (2020)
  • Author(s): Tsukigawa Kenji、Imoto Shuhei、Yamasaki Keishi、Nishi Koji、Tsutsumi Toshihiko、Yokoyama Shoko、Ishima Yu、Otagiri Masaki
  • Journal Title: Pharmaceuticals Volume: 14 Issue: 1 Pages: 22-22
  • DOI: 10.3390/ph14010022
  • Peer Reviewed / Open Access
• [Journal Article] Preparation, Characterization, and in Vitro/in Vivo Evaluation of Paclitaxel-Bound Albumin-Encapsulated Liposomes for the Treatment of Pancreatic Cancer (2019)
  • Author(s): Okamoto Yuko、Taguchi Kazuaki、Sakuragi Mina、Imoto Shuhei、Yamasaki Keishi、Otagiri Masaki
  • Journal Title: ACS Omega Volume: 4 Issue: 5 Pages: 8693-8700
  • DOI: 10.1021/acsomega.9b00537
  • Peer Reviewed / Open Access
• [Journal Article] Investigation of anti-tumor effect of doxorubicin-loaded human serum albumin nanoparticles prepared by a desolvation technique. (2019)
  • Author(s): Kimura K, Yamasaki K, Nishi K, Taguchi K, Otagiri M
  • Journal Title: Cancer Chemother Pharmacol. Volume: 83 Issue: 6 Pages: 1113-1120
  • DOI: 10.1007/s00280-019-03832-3
  • Peer Reviewed
• [Journal Article] Cell-penetrating mechanism of intracellular targeting albumin: Contribution of macropinocytosis induction and endosomal escape (2019)
  • Author(s): Ichimizu Shota、Watanabe Hiroshi、Maeda Hitoshi、Hamasaki Keisuke、Ikegami Komei、Chuang Victor Tuan Giam、Kinoshita Ryo、Nishida Kento、Shimizu Taro、Ishima Yu、Ishida Tatsuhiro、Seki Takahiro、Katsuki Hiroshi、Futaki Shiroh、Otagiri Masaki、Maruyama Toru
  • Journal Title: Journal of Controlled Release Volume: 304 Pages: 156-163
  • DOI: 10.1016/j.jconrel.2019.05.015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Albumin domain mutants with enhanced Aβ binding capacity identified by phage display analysis for application in various peripheral Aβ elimination approaches of Alzheimer's disease treatment (2019)
  • Author(s): Ishima Yu、Mimono Ai、Tuan Giam Chuang Victor、Fukuda Tetsuya、Kusumoto Kohshi、Okuhira Keiichiro、Suwa Yoshiaki、Watanabe Hiroshi、Ishida Tatsuhiro、Morioka Hiroshi、Maruyama Toru、Otagiri Masaki
  • Journal Title: IUBMB Life Volume: 72 Issue: 4 Pages: 641-651
  • DOI: 10.1002/iub.2203
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Design and tuning of a cell-penetrating albumin derivative as a versatile nanovehicle for intracellular drug delivery (2018)
  • Author(s): Ichimizu Shota、Watanabe Hiroshi、Maeda Hitoshi、Hamasaki Keisuke、Nakamura Yuka、Chuang Victor Tuan Giam、Kinoshita Ryo、Nishida Kento、Tanaka Ryota、Enoki Yuki、Ishima Yu、Kuniyasu Akihiko、Kobashigawa Yoshihiro、Morioka Hiroshi、Futaki Shiro、Otagiri Masaki、Maruyama Toru
  • Journal Title: Journal of Controlled Release Volume: 277 Pages: 23-34
  • DOI: 10.1016/j.jconrel.2018.02.037
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Thioredoxin-albumin fusion protein prevents copper enhanced zinc-induced neurotoxicity via its antioxidative activity. (2018)
  • Author(s): Tanaka KI, Shimoda M, Chuang VTG, Nishida K, Kawahara M, Ishida T, Otagiri M, Maruyama T, Ishima Y.
  • Journal Title: Int J Pharm. Volume: 535 Issue: 1-2 Pages: 140-147
  • DOI: 10.1016/j.ijpharm.2017.11.012
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 一酸化窒素とチオールを基軸とした新規NASH治療法の開発 (2022)
  • Author(s): 前田仁志、異島優、小田切優樹、渡邊博志、丸山徹
  • Organizer: 日本薬学会第142年会
• [Presentation] 酸性環境応答性を発揮するアルブミン結合型抗がん剤の作製と抗腫瘍効果 (2022)
  • Author(s): 月川健士、井本修平、今村思音、入江直樹、西 弘二、堤 敏彦、横山祥子、小田切優樹、山崎啓之
  • Organizer: 日本薬学会第142年会
• [Presentation] がん間質細胞を標的とするDDS担体の開発 (2021)
  • Author(s): 前田仁志、水田夕稀、異島優、渡邊博志、小田切優樹、丸山徹
  • Organizer: 第28回日本血液代替物学会年次大会
• [Presentation] がん間質細胞を二重標的化する抗がん剤送達キャリアの開発と新規がんDDS戦略の構築 (2021)
  • Author(s): 水田夕稀、前田仁志、皆吉勇紀、一水翔太、木下遼、異島優、渡邊博志、小田切優樹、丸山徹
  • Organizer: 第37回日本DDS学会学術集
• [Presentation] アルブミン内包リポソームの設計と評価：アルブミン内封量に及ぼす脂質電荷の影響 (2021)
  • Author(s): 長谷川喬史、西弘二、岡本侑子、田口和明、月川健士、小田切優樹、山﨑啓之
  • Organizer: 日本薬学会第141年会
• [Presentation] ヒト膵がん細胞に対するニトロ化フェニル酪酸の細胞死誘導効果 (2021)
  • Author(s): 西 弘二、別府 拓豪、井本 修平、異島 優、月川 健士、小田切 優樹、山崎 啓之
  • Organizer: 日本薬学会第141年会
• [Presentation] 酸性環境応答性を有するアルブミン結合型抗がん剤の作製と評価 (2021)
  • Author(s): 月川 健士、井本 修平、西 弘二、堤 敏彦、横山 祥子、小田切 優樹、山﨑 啓之
  • Organizer: 日本薬学会第141年会
• [Presentation] アルブミン内包リポソームの設計と評価：アルブミン内封量に及ぼす脂質電荷の影響 (2021)
  • Author(s): 長谷川 喬史、西 弘二、岡本 侑子、田口 和明、月川 健士、小田切 優樹、山﨑 啓之
  • Organizer: 日本薬学会第141年会
• [Presentation] 一酸化炭素付加機能性赤血球は包括的に急性腎障害の病態を改善する (2020)
  • Author(s): 永崎 太清、田口 和明、柳澤 洋輝、西田 健人、前田 仁志、酒井 宏水、渡邊 博志、深川 雅史、小田切 優樹、丸山 徹
  • Organizer: 第27回日本血液代替物学会年次大会
• [Presentation] 存赤血球輸血が肝cytochromeP450に与える影響 (2020)
  • Author(s): 田口 和明、得能 正裕、山崎 啓之、小田切 優樹
  • Organizer: 第27回日本血液代替物学会年次大会
• [Presentation] 潰瘍性大腸炎モデルマウスにおけるラクトフェリンナノ粒子の治療効果 (2020)
  • Author(s): 田口 和明、橋本 麻衣、中山 真雪、榎木 裕紀、西 弘二、松元 一明、瀬尾 量、小田切 優樹、山﨑 啓之
  • Organizer: 日本薬剤学会第35年会
• [Presentation] B型肝炎ウイルス新規治療候補薬の健常ラット及び腎障害モデルラットにおける体内動態解析 (2020)
  • Author(s): 橋本 麻衣、田口 和明、山﨑 啓之、井本 修平、満屋 裕明、小田切 優樹
  • Organizer: 日本薬剤学会第35年会
• [Presentation] 一酸化炭素結合型ヘモグロビン小胞体の閉塞性細気管支炎に対する有効性評価 (2020)
  • Author(s): 渡部 佑樹、田口 和明、榎木 裕紀、酒井 宏水、丸山 徹、小田切 優樹、河野 光智、松元 一明
  • Organizer: 日本薬剤学会第35年会
• [Presentation] ヘモグロビンを担体とした一酸化炭素デリバリーシステムによる腎疾患治療戦略 (2020)
  • Author(s): 永﨑 太清、前田 仁志、田口 和明、柳澤 洋輝、西田 健人、酒井 宏水、深川 雅史、渡邊 博志、小田切 優樹、丸山 徹
  • Organizer: 日本薬剤学会第35年会
• [Presentation] 潰瘍性大腸炎モデルマウスにおけるラクトフェリンナノ粒子の治療効果 (2020)
  • Author(s): 渡部 佑樹、田口 和明、榎木 裕紀、酒井 宏水、丸山 徹、小田切 優樹、河野 光智、松元 一明
  • Organizer: 日本薬剤学会第35年会
• [Presentation] 脱溶媒和法により調製したドキソルビシン封入ヒト血清アルブミンナノ粒子の抗腫瘍効果に関する検討 (2019)
  • Author(s): 山崎啓之、木村虎太郎、西弘二、猪原彩希、大島千佳、井本修平、田口和明、小田切優樹
  • Organizer: 第35回日本DDS学会学術集会
• [Presentation] Pharmaceutical properties and potential application of recombinant human albumin dimer as a nanomedicine carrier (2019)
  • Author(s): Masaki Otagiri
  • Organizer: AFPS-ICAPPS conference
  • Int'l Joint Research
• [Presentation] Human Albumin Based Drug Delivery: SNO-Albumin dimer for cancer therapeutic application (2019)
  • Author(s): Masaki Otagiri
  • Organizer: The 17th International Symposium on Blood Substitutes and Oxygen Therapeutics (XVII-ISBS-2019)
• [Presentation] Albumin fusion protein: next generation of albumin preparation (2019)
  • Author(s): Toru Maruyama, Masaki Otagiri
  • Organizer: The 17th International Symposium on Blood Substitutes and Oxygen Therapeutics (XVII-ISBS-2019)
• [Presentation] Study of structtual-chemistry of sodium 4-phenylbutyrate on its binding to serum albumin. (2018)
  • Author(s): Masaki Otagiri, Keishi Yamasaki
  • Organizer: Annual European Pharma Congress
  • Int'l Joint Research / Invited
• [Presentation] Pharmaceutical Application of Recombinant Human Serum Albumin Dimer (2018)
  • Author(s): Masaki Otagiri, Kazuaki Taguchi, Keishi Yamasaki, Yu Ishima, Toru Maruyama
  • Organizer: SICHEM2018
  • Int'l Joint Research / Invited
• [Presentation] 腫瘍関連マクロファージを標的とした新規DDS担体の開発 (2018)
  • Author(s): 水田 夕稀、前田 仁志、異島 優、皆吉 勇紀、一水 翔太、木下 遼、渡邊 博志、小田切 優樹、丸山 徹
  • Organizer: 第34回日本DDS学会学術集会